Brensocatib, an oral, competitive, and reversible inhibitor of dipeptidyl peptidase 1 (DPP1), reduces exacerbations and lung function decline in non-cystic fibrosis bronchiectasis (NCFBE). This study aimed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of brensocatib in adults with cystic fibrosis (CF), comparing these findings with data from previous trials in healthy adults and in those with NCFBE to inform dose selection for future clinical trials. A phase IIa, single-blind, randomized, placebo-controlled trial was conducted to assess the PK, PD, safety, and tolerability of brensocatib in adults with CF. Participants were randomly assigned to receive once-daily brensocatib (10 mg, 25 mg, or 40 mg) or placebo for 28 days. The study planned enrollment of up to 34 adults, stratified on the basis of their CF transmembrane conductance regulator (CFTR) modulator use, to evaluate the PK profile of brensocatib and its safety compared with placebo. Primary PK parameters, including maximum plasma concentration (Cmax), time to maximum concentration (Tmax), area under the concentration-time curve from 0 to 24 h (AUC0-24), and half-life (t1/2), were determined on day 1 and day 28. Dose-dependency of brensocatib exposure was analyzed, and safety and tolerability were assessed through treatment-emergent adverse events. Data from participants were compared with previous data from healthy adults and from those with NCFBE. A total of 29 participants were randomized to treatment, with 21 stratified to the CFTR modulator group. Baseline characteristics were similar among cohorts. Mean age was 37.9 (standard deviation (SD) 14.6) years, and most participants exhibited mild-to-moderate lung disease. PK analysis showed dose-dependent and predictable brensocatib exposure, with comparable profiles between participants with and without use of CFTR modulators. In addition, PK profiles in participants were comparable to those of healthy adults and of those with NCFBE. Pharmacodynamic analysis revealed dose-dependent reduction in neutrophil serine protease (NSP) activity, reaching saturation around the 25-mg dose, particularly in blood. Brensocatib at all doses was well tolerated with no new identified safety signals. Brensocatib demonstrated consistent PK profiles independent of CFTR therapy and comparable to those of healthy and NCFBE adults. Brensocatib reduced blood and sputum NSP levels. The safety profile was comparable to previous studies, with no new safety concerns identified, supporting the use of similar dosing for adults with CF as for other populations. These findings advocate for further investigation of brensocatib in CF. NCT05090904.
Konstan et al. (Sun,) studied this question.